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TTP

Target Product Profile Decisions

Decision percentages when tau_LRV = tau_TV = 0.025
nk NO-GO Continue GO
Slope, %: -10%
20 0.44 0.56 0.00
30 0.60 0.40 0.00
40 0.72 0.28 0.00
60 1.00
80 1.00
Slope, %: 10%
20 0.08 0.83 0.09
30 0.12 0.76 0.12
40 0.15 0.69 0.16
60 0.35 0.24 0.41
80 0.41 0.07 0.52
Slope, %: 20%
20 0.02 0.73 0.25
30 0.03 0.61 0.36
40 0.03 0.51 0.46
60 0.04 0.05 0.91
80 0.02 0.00 0.98
Slope, %: 30%
20 0.01 0.49 0.50
30 0.00 0.36 0.63
40 0.00 0.22 0.78
60 0.00 1.00
80 1.00
Slope, %: 40%
20 0.00 0.29 0.71
30 0.00 0.12 0.88
40 0.04 0.96
60 1.00
80 1.00
When theta_lrv = 0, theta_TV = 20, tau_LRV = tau_TV = 0.025.

When theta_lrv = 0, theta_TV = 20, tau_LRV = tau_TV = 0.025.

Ranking

\(\psi_1\): Comparing Against Control

\(f(\psi_2)\): Comparing estimated confidence in top 2 regimens

\(\psi_3\): Posterior probability of ranking in top 2

Together

  • TTP (high-low) and Mixed survival rates such that:
    • Regimen 1 (control): 5% relapse rate, reference log10(TTP) slope
    • Regimen 2 (sub-optimal regimen): 10% relapse rate, -10% relative log10(TTP) slope
    • Regimen 3 (minimal regimen): 5% relapse rate, 10% relative log10(TTP) slope
    • Regimen 4 (minimal regimen): 5% relapse rate, 35% relative log10(TTP) slope
    • Regimen 5 (desirable regimen): 2.5% relapse rate, 40% relative log10(TTP) slope

Stopping sub-optimal regimens

Stopping based on:

  • TTP decision: NO-GO
  • P(rank in top 2) < 60%
  • Relapses >= 2
Slope Stop relapse Stop TPP P(top 2) < 0.6 Stop relapse or TPP Stop relapse or TPP or P(top 2) < 0.6
-10% 0.205 0.603 1.000 0.686 1
10% 0.232 0.112 0.977 0.317 1
20% 0.210 0.028 0.824 0.236 1

De-prioritizing sub-optimal regimens

De-prioritizing based on:

  • TTP decision: NO-GO, Continue
  • P(rank in top 2) < 60%
  • Relapses >= 2
Slope Stop relapse Stop TPP P(top 2) < 0.6 Stop relapse or TPP Stop relapse or TPP or P(top 2) < 0.6
-10% 0.205 0.998 1.000 0.998 1
10% 0.232 0.875 0.977 0.902 1
20% 0.210 0.640 0.824 0.720 1

Desirable regimens

Slope GO relapse GO TPP P(top 2) >= 0.6 GO relapse and TPP GO relapse and TPP and P(top 2) >= 0.6
-10% 1.00 0.002 0.000 0.002 0.000
10% 1.00 0.123 0.014 0.123 0.123
20% 0.79 0.360 0.176 0.280 0.280

Single Example

Interim results from a single simulated phase 2B study with thirty partients per regimen. The target product profile (TPP) assumes \(\theta_{LRV} = 0, \theta_{TV} = 20, \tau_{LRV} = \tau_{TV} = 0.025\).
Interim 1
Regimen Duration No. patients No. relapses \(\hat{\theta}_{0.5}\) \(\hat{\theta}_{0.025}\) \(\hat{\theta}_{0.975}\) TPP decision \(\hat{\psi}_1\) \(\hat{\psi}_2\) \(\hat{\psi}_3\)
1 26 30 0 0.000 0.022
2 16 30 1 0.111 -0.129 0.422 Continue 0.808 0.001 0.026
3 16 30 0 0.233 -0.012 0.569 Continue 0.966 0.004 0.240
4 16 30 0 0.319 0.054 0.688 GO 0.991 0.048 0.715
5 16 30 0 0.556 0.257 0.950 GO 1.000 0.947 0.997

Frequentist summaries

P(top regimen has steepest estimated slope)

condition nk p.true.present
Even 20 0.914
Even 30 0.968
Even 40 0.981
Even 60 1.000
Even 80 1.000
High 20 0.601
High 30 0.648
High 40 0.661
High 60 0.768
High 80 0.786
High-low 20 0.966
High-low 30 0.994
High-low 40 0.998
High-low 60 1.000
High-low 80 1.000
condition nk prop Regimen
Even 20 0.002 Regimen 1
Even 20 0.011 Regimen 2
Even 20 0.065 Regimen 3
Even 20 0.250 Regimen 4
Even 20 0.672 Regimen 5
Even 30 0.003 Regimen 2
Even 30 0.042 Regimen 3
Even 30 0.202 Regimen 4
Even 30 0.753 Regimen 5
Even 40 0.024 Regimen 3
Even 40 0.183 Regimen 4
Even 40 0.793 Regimen 5
Even 60 0.069 Regimen 4
Even 60 0.931 Regimen 5
Even 80 0.035 Regimen 4
Even 80 0.965 Regimen 5
High 20 0.183 Regimen 2
High 20 0.220 Regimen 3
High 20 0.271 Regimen 4
High 20 0.326 Regimen 5
High 30 0.144 Regimen 2
High 30 0.210 Regimen 3
High 30 0.262 Regimen 4
High 30 0.384 Regimen 5
High 40 0.142 Regimen 2
High 40 0.193 Regimen 3
High 40 0.291 Regimen 4
High 40 0.374 Regimen 5
High 60 0.069 Regimen 2
High 60 0.184 Regimen 3
High 60 0.277 Regimen 4
High 60 0.470 Regimen 5
High 80 0.066 Regimen 2
High 80 0.146 Regimen 3
High 80 0.266 Regimen 4
High 80 0.522 Regimen 5
High-low 20 0.001 Regimen 1
High-low 20 0.009 Regimen 3
High-low 20 0.369 Regimen 4
High-low 20 0.621 Regimen 5
High-low 30 0.003 Regimen 3
High-low 30 0.345 Regimen 4
High-low 30 0.652 Regimen 5
High-low 40 0.347 Regimen 4
High-low 40 0.653 Regimen 5
High-low 60 0.228 Regimen 4
High-low 60 0.772 Regimen 5
High-low 80 0.190 Regimen 4
High-low 80 0.810 Regimen 5
Frequentist summary of estimator performance across changes in sample size (nk) and differences in $\log_{10}$(TTP) slope. For all panels, results are based on 1,000 simulated datasets were used for each sample size and condition. A) The proportion of simulations where a given regimen was estimated to have the steepest slope. B) The proportion of simulations where the steepest estimated slope belonged to one of the true top two steepest regimens. C) The proportion of simulations (y-axis) where the estimated control slope falls outside of the estimated 95\% confidence interval for a regimen with a given effect size (x-axis).

Frequentist summary of estimator performance across changes in sample size (nk) and differences in \(\log_{10}\)(TTP) slope. For all panels, results are based on 1,000 simulated datasets were used for each sample size and condition. A) The proportion of simulations where a given regimen was estimated to have the steepest slope. B) The proportion of simulations where the steepest estimated slope belonged to one of the true top two steepest regimens. C) The proportion of simulations (y-axis) where the estimated control slope falls outside of the estimated 95% confidence interval for a regimen with a given effect size (x-axis).